Project Summary/Abstract Despite a dire need for successful treatment and prevention strategies for Alzheimer?s Disease, no disease- modifying therapies have been successfully brought to market. The Accelerating Medicines Partnership in Alzheimer?s Disease Target Discovery project (AMP-AD) is working to identify candidate targets with potential therapeutic impact by querying AD-induced changes in molecular state on a systems level. Computational models of disease have emerged across six AMP-AD projects. Despite high-level consensus across models, initial efforts have identified largely non-overlapping sets of driver genes likely to regulate disease perturbation of network state. This supplemental project builds on the parent grant goal to accelerate characterization and validation of high-confidence AMP-AD targets through the development and open dissemination of computational and experimental tools necessary for their validation. Effective target validation requires a combination of complementary approaches for target manipulation, including expression modulation, chemical probes, genetics, and systems biology. This work aims to reduce the risks and to form a solid basis for target validation through chemical biology. Target Enabling Packages (TEPs) developed within this project are designed to bridge the gap between identification of candidate targets, and the ability to launch a chemical biology or drug discovery program. In order to effectively serve these targets, we propose to expand the repertoire of our team to include expertise for the development of small molecules and peptides designed to disrupt protein-protein interactions. This one year supplement will evaluate the capabilities and utility of this work by focusing on the three FERM domain-containing AMP-AD target proteins (FERMMT2, EPB41L3, and Moesin) that interact with CD44 to develop tools for experimental validation of these AMP-AD targets.